鉛化物是普遍存在的環境毒性物質，長期暴露會促使動物腎臟、腦及肺臟組織產生腫瘤。流行病學也指出鉛化物為可能之人類致癌物質。先前研究發現，醋酸鉛能藉由持續性活化之ERK1/2訊號而增加核苷酸切除修補能力及降低細胞毒性及基因突變。此外，醋酸鉛的基因毒性會因細胞含低量的APE/Ref-1而增高，APE/Ref-1參與鹼基切除修補途徑以及氧化還原調控轉錄因子如AP-1、NF-κB，以及p53的活化。本論文研究探討ERK1/2訊號及APE/Ref-1在醋酸鉛引發人類非小型肺癌細胞CL3之基因表現的角色。以MKK1/2抑制劑U0126來操控細胞內ERK1/2訊號的活化，並以APE/Ref-1含量較低50%之APEas-CL3細胞株及其對照組Babe-CL3細胞株來檢測APE/Ref-1對基因表現的影響。利用一套自製且有品質管控的基因微陣列技術，我們篩選出受醋酸鉛而引發表現的一些基因，且其等之表現量與ERK1/2訊號及APE/Ref-1含量有關。從其中，我們挑選PEA15做進一步研究，文獻指出PEA15能增加ERK1/2在細胞質的分布。我們進而利用反轉錄配合一般及即時聚合酶連鎖反應和西方墨點法分析檢測PEA15的基因表現及蛋白含量，實驗結果證實醋酸鉛能透過ERK1/2訊號誘發PEA15的基因表現及蛋白含量，推測此途徑可能涉及ERK1/2之負回饋迴路調控機轉。此外，APEas-CL3細胞之內生性PEA15基因表現量及蛋白質含量明顯地低於Babe-CL3細胞，而醋酸鉛對Babe-CL3細胞及APEas-CL3細胞均能誘發PEA15的基因表現。綜合而言，我們在本研究中建立了一套基因微陣列技術，並且篩選出一些候選基因以供未來在闡明ERK1/2訊號及APE/Ref-1調控醋酸鉛毒理的角色做深入的研究。

Lead compounds are widely distributed environmental toxicants. Long-term lead exposure causes kidney, brain, and lung cancer in animals. Epidemiological studies indicate that lead is a possible human carcinogen. Previous studies have shown that sustained ERK1/2 activation elicited by lead acetate (Pb(II)) enhances nucleotide excision repair synthesis and confers anti-cytotoxicity and anti-mutagenicity. Moreover, Pb(II) genotoxicity is enhanced when cells have low level of apurinic/apyridimic endonuclease/redox factor-1 (APE/Ref-1), an enzyme functioning in the DNA base excision repair pathway and the redox activation of transcription factors such as AP-1, NF-κB and p53. In this study, we investigate the roles of ERK1/2 signal and APE/Ref-1 in gene expression profiling caused by lead acetate in human non-small adenocarcinoma CL3 cells. The cellular ERK1/2 activation was modulated using U0126, an inhibitor of MKK1/2. The involvement of APE/Ref-1 in gene expression was examined using APEas-CL3 cell line whose APE/Ref-1 level was 50% as comparison with its counterpart Babe-CL3. By using a home-made cDNA microarray with systemic quality control, we have screened a list of Pb(II)-induced genes whose expression were associated with ERK1/2 signal or APE/Ref-1 levels. Among them, PEA15 that can enhance ERK1/2 localization in the cytosol was selected for further investigation. We next adopted reverse transcription coupled with polymerase chain reaction (PCR) or real-time PCR and Western blotting to examine the gene expression and protein levels of PEA15. The results confirmed that Pb(II) can induce PEA15 gene expression and protein levels via ERK1/2 signal. This finding suggests that a negative feedback regulation of ERK1/2 is achieved by induction of PEA15 expression. On the other hand, the PEA15 gene expression and protein levels in APEas-CL3 cells were markedly lower than those in Babe-CL3 cells, suggesting APE/Ref-1 mediates in inducing PEA15 gene expression. Pb(II) could induce PEA15 gene expression and protein levels in both APEas-CL3 and Babe-CL3 cells. Taken together, we have established a cDNA microarray system and obtained several candidate genes for further investigation of the roles of ERK1/2 signal and APE/Ref-1 in Pb(II) toxicology.

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